Effect of Parathyroid Function After Thyroidectomy and Radioactive-Iodine Therapy for Thyroid Disease

The thyroid gland is the largest endocrine gland in the human body. It secretes thyroid hormones that affect the metabolism. Hyperthyroidism including Graves’ disease (GD), toxic multinodular goiter (TMNG), toxic adenoma (TA) and differentiated thyroid cancer (DTC) are common thyroid diseases, for which thyroidectomy and radioactive iodine (RAI) treatment can be used. The parathyroid gland is an endocrine organ, which consists of 4 small glands located posteriorly to the thyroid in the middle aspect of the anterior neck and secretes parathyroid hormone (PTH), a polypeptide in response to low calcium levels detected in the blood. Low calcium can lead to circumoral or peripheral paranesthesia, tetany, carpopedal spasm, laryngospasm, and ECG changes from long QT interval to VT arrest [1,2]. While high calcium can cause fatigue, polyuria, polydipsia, nephrolithiasis, peptic ulcer disease, altered mental status, gait instability [3-5], myalgia, arthralgia, abdominal pain [4], rare submandibular gland atrophy and sialolithiasis, metastatic pulmonary calcification [6,7], sometimes even inducing acute kidney injury or acute pancreatitis [8-13], or being life-threatening [14,15].

carcinoma" and "parathyroid gland" or "calcium" or "parathyroid hormone (PTH)" to summarize the effect of thyroidectomy and RAI on parathyroid gland function in patients with above mentioned benign and malignant thyroid diseases.

Effect of Thyroidectomy on Parathyroid Function
Thyroidectomy meaning partial or complete removal of thyroid tissue is among the most frequently performed surgical procedures in general surgery for thyroid disease including differentiated thyroid carcinoma (DTC) and hyperthyroidism. Postoperative hypocalcemia due to hypoparathyroidism is the most common complication of thyroidectomy, with a reported incidence of 1.6% -50% [16][17][18]. It is reported that post-operative hypocalcemia is frequently occurred in the first and second post-operative days. Permanent hypoparathyroidism after total thyroidectomy is associated with an increased risk of death [19]. Hypocalcemia after thyroidectomy for benign diseases, apart from more frequent symptoms of hypocalcemia in patients with Graves' disease, there were no differences in the overall frequency of biochemical hypocalcemia or decreasing PTH among benign and malignant thyroid diseases [20,21]. Generally thyroidectomy for hyperthyroidism rendered a patient to an euthyroid state faster than RAI [22]. After surgery for hyperthyroidism, young age, operative time, type of hospital, and parathyroid auto-transplantation were associated with early postoperative hypocalcemia [23].
Incidental parathyroidectomy with a reported incidence of 6.4% -31.1%, was thought to be associated with postoperative hypocalcemia. Central neck dissection, total thyroidectomy, larger thyroid dimensions, extrathyroidal extension, tumor diameter more than 10mm, autoimmune thyroid disease, substernal goiter, females' gender were found to be significant risk factors of incidental parathyroidectomy [24][25][26][27][28][29]. Operative time and the amount of bleeding were not the risk factors [30]. However, in the study by Chew C, they found incidental parathyroidectomy did not contribute to significant changes in postoperative serum calcium  The specific mechanism of hyperparathyroidism after RAI treatment is still unclear, but the main risk factors may be related to age and treatment dose. Triggs and Williams [69] reported a high frequency of parathyroid adenomas in newborn rats after RAI treatment within 2 days of life. In addition, S Hanthi M [70] found that the older the patients were treated with RAI, the shorter the incubation time of developing hyperparathyroidism was. The parathyroid of older patients was more sensitive to RAI, which may be related to the instability of genes, thus leading to damage of apoptosis mechanism [71]. On the contrary, the younger the age of radiation exposure, the more likely it is to develop thyroid cancer earlier [72]. In the study by Piotr Szumowski [73]

Effect of RAI Treatment on Parathyroid Function For DTC Patients
DTC is a common endocrine malignancy; the yearly incidence of DTC has nearly tripled from 4.9 per 100000 in 1975 to 14.3 per in 2009. One study predicted that PTC will become the third most common cancer in women by 2019 [84,85]. It is suggested that radiation exposure is associated with the development of thyroid carcinoma, especially the thyroid radiated directly by the irradiation dose (more than 50 -100mGy). The smaller the contact's ageand the greater the risk of thyroid cancer was [72]. This could be one of the reasons of the rising incidence of thyroid cancer. Other factors may include increased sensitivity of ultrasound scan, iodine intake, and compounds with carcinogenic potential, such as a large class of xneobiotics (flame retardants, pesticides, repellents, or thermal insulators) [86]. Currently, thyroid surgery, RAI treatment and TSH inhibition therapy have become the standard treatment regimen for DTC patients. Total thyroidectomy combined with RAI treatment will improve the overall treatment efficiency and enable patients to have higher quality of life [87].
RAI treatment following thyroidectomy is suggested for many DTC patients. The purpose of RAI treatment is to remove residual thyroid and small metastatic lesions, to facilitate postoperative follow-up and recurrence monitoring. High-dose RAI therapy is associated with decreased risk of recurrence in high-risk papillary thyroid cancer [88]. It is now accepted that the RAI treatment is very safe and the advantages of treating DTC with RAI outweigh the disadvantages [89]. Treatment with RAI can produce early and late complications. The common early complications include swelling and discomfort in the neck, xerostomia, dry eye, abnormalities of taste and smell, dysphagia, nausea, vomiting, bone marrow suppression [90], gonadal damage (hypospermia or temporary amenorrhea/oligomenorrhea), nasal dryness and obstruction, and nasolacrimal obstruction [91][92][93][94][95][96]. The late complications include permanent salivary gland dysfunction, leukemia and secondary malignancy, pulmonary fibrosis, fertility problems [97][98][99][100][101][102].
The parathyroid gland is an adjacent organ of the thyroid.
Theoretically, RAI may influence parathyroid function. In the study by Aytekin Guven [103], 19 DTC patients after RAI therapy (therapeutic dose 100 -150mCi) were measured PTH, blood calcium, phosphorus at the first, third, sixth, twelfth month. PTH gradually decreased between the first and sixth month, but in the normal range, and restored baseline at twelfth month. Blood calcium level was similar to this trend without significant difference. Some patients appeared hypocalcemia without any clinical symptoms.
Zhi-hua Zhao et al. [104] found there were still hypoparathyroidism happened after RAI treatment and the changes of PTH and blood calcium before and after the RAI treatment were not statistically significant. Generally, PTH reduced after RAI treatment for DTC, and a small number of patients could appear hypocalcemia. The underlying mechanism of diminished parathyroid function after RAI by a non-targeted effect of ionizing radiation called a "bystander effect" on the adjacent cells (RIBE) [103,105]. Gene expression changes may lead to RIBE occurrence [106]. There was one case reported that a patient developed hyperparathyroidism after RAI treatment for DTC. A 17-year-old male patient with thyroid papillary carcinoma underwent 2 times RAI treatment (total doses 263 mCi). Two years after RAI treatment, a parathyroid adenoma was detected by a neck ultrasound examination.
The specific risk factors that influence on the parathyroid gland function after RAI treatment for DTC are still needed to be further studied. Glazebrook G [107] found that age, sex, thyroid gland excision scope, operation method, iodine doses, neck radiation exposure, relative location between thyroid and parathyroid were not relevant risk factors of low parathyroid gland function. Aytekin Guven [103] found that age, gender, iodine dose had no impact on the PTH changes both before and after RAI therapy. Currently, the effect of RAI treatment on parathyroid gland function is not very clear yet. The studies mainly focused on the changes of PTH, blood calcium and blood phosphorus at different stages before and after the treatment of RAI. The sample sizes in these studies were small and the intervals of PTH and blood calcium measurement were different among different studies. No systematic study was published focusing on long-term (over one year) changes of PTH.

Conclusion
To sum up, thyroidectomy and RAI treatment may influence the parathyroid function in GD, TMNG, TA and DTC patients.

Conflict of Interest
No conflict of interest.